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Articles 1 - 15 of 15
Full-Text Articles in Medical Pharmacology
Cb1 Allosteric Modulation: Preclinical Insights Into Therapeutic Potential And Misuse Liability, Mohammed A. Mustafa
Cb1 Allosteric Modulation: Preclinical Insights Into Therapeutic Potential And Misuse Liability, Mohammed A. Mustafa
Theses and Dissertations
Cannabinoid type-1 (CB1) allosteric modulators represent a promising approach to modulate CB1 receptor signaling by binding to distinct receptor sites, without producing adverse cannabimimetic and dependence-related effects associated with Δ9-tetrahydrocannabinol (THC) and other CB1 agonists. This dissertation investigates the pharmacological, behavioral, and dependence-related profiles of CB1 allosteric modulators for their therapeutic potential and misuse liability. Presented here, the chiral CB1 positive allosteric modulator (PAM) ZCZ011 was resolved into its R- and S-enantiomers and characterized across in vitro and in vivo assays. Both enantiomers enhance CB1 agonist activity and produce intrinsic effects in vitro. Behaviorally, they produce antinociceptive effects in the …
In Vivo Effects Of The Cb1 Allosteric Modulator Ldk1258, A Structural Analog Of Org-27569, Mohammed A. Mustafa
In Vivo Effects Of The Cb1 Allosteric Modulator Ldk1258, A Structural Analog Of Org-27569, Mohammed A. Mustafa
Theses and Dissertations
CB1 receptor allosteric modulators are an area of growing interest for their potential novel therapeutic actions. In the present study, we examined LDK1258 in a series of pharmacological in vivo tests sensitive to CB1 receptor stimulation. In the tetrad assay, LDK1258 produced significant decreases in locomotor activity and body temperature measures but did not produce either antinociception as measured in the tail-withdrawal assay or catalepsy as assessed in the bar test. These same effects were observed in both CB1 (-/-) and (+/+) mice. Moreover, LDK1258 failed to shift the dose-response curves of two orthosteric CB1 receptor agonists in the triad …
Cannabidiol, Behavior, And Immune Biomarkers In Idiopathic Autism Spectrum Disorder., Sarah Huang Shrader
Cannabidiol, Behavior, And Immune Biomarkers In Idiopathic Autism Spectrum Disorder., Sarah Huang Shrader
Electronic Theses and Dissertations
Autism Spectrum Disorder (ASD) is a highly heterogenous neurodevelopmental disorder currently estimated by the CDC to affect 1 in 36 children in the U.S.. This uniquely human condition is characterized by a spectrum of symptoms that feature social communication deficits and repetitive behaviors with restricted interest. Autistic individuals commonly exhibit multiple comorbidities, including attention deficit hyperactivity disorder, anxiety, and seizures, which can complicate an already multi-faceted presentation. The majority of ASD cases are idiopathic in nature. Developing a well-validated animal model of ASD for translational research comes with many challenges, but is crucial for advancing our understanding of autism and …
Characterization Of Novel Cannabinoid Receptor 2-Selective Agonists At The Biochemical And Cellular Levels: Leads For Therapeutic Agents, Ashley M. Hine
Characterization Of Novel Cannabinoid Receptor 2-Selective Agonists At The Biochemical And Cellular Levels: Leads For Therapeutic Agents, Ashley M. Hine
Honors Scholar Theses
Putative cannabinoid receptor 2 (CB2)-selective agonists were identified from a library of commercially available compounds via inhibition of cAMP accumulation in high throughput screening. Binding affinity and receptor subtype selectivity were assessed using heterologous competition binding assays against the known cannabinoid orthosteric ligand CP55940. Test compounds ASX0152383 and CSC003141 preferentially bound to CB2, with no detection of binding to CB1 up to 1 mM. CMB038865 exhibited nearly 100-fold selectivity for CB1 over CB2, while CZ000026 bound non-preferentially to both receptors in the low micromolar range. To determine the extent of G protein …
Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery
Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery
Theses and Dissertations
The potential antitumor activity of mixed CB1/CB2 cannabinoid receptor agonists, such as the aminoalkylindole WIN55,212-2 (WIN2), has been extensively studied, but little information is available as to their potential interaction with conventional cancer therapies, such as ionizing radiation (IR). In the present work, we investigated the effects of WIN2 on the antiproliferative effects of radiation in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cells, as well as an immortalized human breast epithelial cell line (MCF-10A). WIN2 or radiation alone inhibited breast tumor growth, while the combination of WIN2 and radiation was more effective than either agent alone in …
Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage
Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage
Theses and Dissertations
The effects of cannabinoids in reducing somatic signs of opioid withdrawal have been known for some time. In morphine dependent rodents, opioid withdrawal following precipitation with the mu opioid antagonist naloxone elicits robust withdrawal behaviors including jumps, paw flutters, head shakes, diarrhea and weight loss. Delta-9-tetrahydrocannabinol has been shown to reduce this opioid withdrawal in mice via activation of the cannabinoid type-1 (CB1) receptor and recently it has been shown that inhibition of the catabolic enzymes for endocannabinoids also reduce somatic signs of opioid withdrawal. Specifically, inhibition the enzyme fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid …
Effect Of Cannabinoids On Pain-Stimulated And Pain-Depressed Behavior In Rats, Andrew Kwilasz
Effect Of Cannabinoids On Pain-Stimulated And Pain-Depressed Behavior In Rats, Andrew Kwilasz
Theses and Dissertations
Cannabinoids produce antinociception in many preclinical models of acute and chronic pain. In contrast, cannabinoids produce inconsistent analgesia in humans, showing little or no efficacy in treating acute pain, with modest efficacy in treating chronic inflammatory pain. This discrepancy may reflect an overreliance on preclinical assays of pain-stimulated behaviors, defined as behaviors that increase in rate or intensity following delivery of a noxious stimulus. In these assays, antinociception is indicated by a reduction in pain-stimulated behaviors, and antinociception is produced either by a reduction in sensory sensitivity to the noxious stimulus (i.e. true analgesia) or by false positive motor impairment. …
Differential Roles Of The Two Major Endocannabinoid Hydrolyzing Enzymes In Cannabinoid Receptor Tolerance And Somatic Withdrawal, Joel Schlosburg
Differential Roles Of The Two Major Endocannabinoid Hydrolyzing Enzymes In Cannabinoid Receptor Tolerance And Somatic Withdrawal, Joel Schlosburg
Theses and Dissertations
While there is currently active debate over possible therapeutic applications of marijuana and cannabis-based compounds, consistently their primary drawbacks have been the psychoactive properties, dependence, and abuse potential. Prolonged administration of ∆9-tetrahydrocannabinol (THC), the primary psychoactive constituent in marijuana, demonstrates both tolerance and physical withdrawal in both preclinical and clinical studies. Repeated THC administration also produces CB1 receptor adaptations in the form of reduced activation of receptors, along with a downregulation of membrane surface receptors, in many brain regions involved in THC-associated behaviors. The increased need for drug to maintain therapeutic effects, and a withdrawal syndrome following discontinuation of use, …
Effects Of Cannabinoid Receptor Interacting Protein (Crip1a) On Cannabinoid Receptor (Cb1) Function, Tricia Smith
Effects Of Cannabinoid Receptor Interacting Protein (Crip1a) On Cannabinoid Receptor (Cb1) Function, Tricia Smith
Theses and Dissertations
EFFECTS OF CANNABINOID RECEPTOR INTERACTING PROTEIN (CRIP1a) ON CANNABINOID (CB1) RECEPTOR FUNCTION. By Tricia Hardt Smith, B.S., M.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2009. Major Director: Dana E. Selley, Ph.D., Department of Pharmacology and Toxicology This dissertation examines modulation of cannabinoid CB1 receptor function by Cannabinoid Receptor Interacting Protein (CRIP1a), a novel protein that binds the C-terminus of CB1 receptors. In Human embryonic kidney cells expressing human CB1 receptors (hCB1-HEK) and hCB1-HEK cells stably co-expressing CRIP1a (hCB1-HEK-CRIP1a), quantitative immunoblotting revealed a CRIP1a/CB1 …
The Effect Of Chronic Constriction Injury On Cellular Systems Within Nociceptive Pathways In The Mouse, Michelle Hoot
The Effect Of Chronic Constriction Injury On Cellular Systems Within Nociceptive Pathways In The Mouse, Michelle Hoot
Theses and Dissertations
Chronic neuropathic pain is often difficult to treat due to its resistance to therapeutic intervention. This is due in part to the poor understanding of the physiological mechanisms involved in the establishment and maintenance of neuropathic pain states. The neuropathic pain model, chronic constriction injury of the sciatic nerve, produced robust pain hypersensitivity in our mice. It also induced significant changes in the mitogen activated protein kinase family, and the cannabinoid and µ-opioid systems in three different brain areas involved in the modulation or regulation of pain states. CCI induced a 2.5 fold increase in mRNA of the kinase Raf-1 …
Cannabinoid Receptor Type 2 Activation Induces A Microglial Anti-Inflammatory Phenotype And Reduces Migration Via Mkp Induction And Erk Dephosphorylation, Edgar A. Romero-Sandoval, Ryan Horvath, Russell P. Landry, Joyce A. Deleo
Cannabinoid Receptor Type 2 Activation Induces A Microglial Anti-Inflammatory Phenotype And Reduces Migration Via Mkp Induction And Erk Dephosphorylation, Edgar A. Romero-Sandoval, Ryan Horvath, Russell P. Landry, Joyce A. Deleo
Dartmouth Scholarship
Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.
A Comparision Of Delta-9-Tetrahydrocannabinol Dependence In C57bl/6j Mice And Fatty Acid Amide Hydrolase Knock Out Mice, Brittany Leigh Alice Carlson
A Comparision Of Delta-9-Tetrahydrocannabinol Dependence In C57bl/6j Mice And Fatty Acid Amide Hydrolase Knock Out Mice, Brittany Leigh Alice Carlson
Theses and Dissertations
The idea that humans and laboratory animals can become physically dependent on marijuana or its primary psychoactive constituent, delta-9-tetrahydrocannabinol (THC), is gaining acceptance. However, there are no currently approved pharmacotherapies to treat cannabinoid withdrawal. The objective of this thesis was to evaluate whether elevating endogenous anandamide levels using mice lacking fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide metabolism, would ameliorate THC dependence. Mice were treated subchronically with a low or high THC dosing regimen and challenged with the CB1 receptor antagonist, rimonabant, to precipitate withdrawal. Following subchronic THC treatment, rimonabant precipitated a significant increase in paw flutters …
Relationship Between Cb1 And S1p Receptors In The Central Nervous System, Lauren Michele Collier
Relationship Between Cb1 And S1p Receptors In The Central Nervous System, Lauren Michele Collier
Theses and Dissertations
There is significant sequence homology and anatomical co-distribution between cannabinoid (CB1) and sphingosine-1-phosphate (S1P) receptors in the CNS, but potential functional relationships between these lysolipid receptors have not been examined. Therefore, to investigate possible relationships between these two systems at the level of G-protein activation, agonist-stimulated [35S]GTPγS binding and autoradiography were conducted. Autoradiographic studies were first performed to localize receptor-mediated G-protein activation in mouse brain. Coronal brain slices were processed for stimulation of [35S]GTPγS binding using the synthetic cannabinoid agonist WIN 55,212-2 (WIN) or SIP. High levels of WIN- and S1P-stimulated [35S]GTPγS binding were observed in the caudate putamen, hippocampus, …
The Influence Of Sustained Cb1 Blockade During Adolescence On Breakpoints In A Progressive-Ratio Paradigm, Mayo Jerry Wright Jr.
The Influence Of Sustained Cb1 Blockade During Adolescence On Breakpoints In A Progressive-Ratio Paradigm, Mayo Jerry Wright Jr.
Theses and Dissertations
The developmental psychopharmacology of cannabinoids is poorly understood and little is known about the developmental consequences of repeated exposure to cannabinoid antagonists. In these experiments, male Long-Evans rats were treated with SR141716A, a cannabinoid antagonist, throughout adolescence and allowed unrestricted access to food. Control groups were treated with vehicle during the same developmental period and allowed either unrestricted access to food or were pair-fed with a member of the SR-treated group. Motivation to work for food was measured in progressive-ratio sessions at varying levels of food deprivation. For rats that consumed fewer calories throughout adolescence, whether because of pharmacological intervention …
The Study Of The Effect Of Drugs Of Abuse On Protein Kinase A Activity In Mouse Brain And Spinal Cord, George D. Dalton
The Study Of The Effect Of Drugs Of Abuse On Protein Kinase A Activity In Mouse Brain And Spinal Cord, George D. Dalton
Theses and Dissertations
Morphine and Δ9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and Δ9-THC produces problematic side-effects including tolerance and physical dependence. The cellular mechanisms underlying opioid and cannabinoid antinociceptive tolerance have been studied for years. Research has demonstrated that the expression of morphine and Δ9-THC antinociceptive tolerance may be mediated through intracellular signaling pathways, such as the adenylyl cyclase /Protein Kinase A (PKA) cascade. The present study investigated the role of PKA in the expression of morphine and Δ9-THC antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or Δ9-THC and the warm-water …